Many of the biomolecular interactions that promote tumorigenesis involve cell surface proteins that mediate both intra- and intercellular signaling. “Tumor markers” are proteins on the surface of a cell that are exclusively expressed, over-expressed or show an altered expression pattern as a result of transformation to a neoplastic state. The surface concentration of certain tumor markers has been correlated to the progression of cancer. For example, the interaction between the cell surface receptor αVβ3 and the cell adhesion molecule vitronectin has been implicated in angiogenesis (Varner J, Cheresh D: Integrins and cancer. Curr Opin Cell Biol, 1996, 8(5): 724-730; Vailhe B, Ronot X, Tracqui P, Usson Y, Tracqui L: In vitro angiogenesis is modulated by the mechanical properties of fibrin gels and is related to αVβ3 integrin localization. In Vitro Cell Dev Biol Anim, 1997, 33(10): 763-773; Horton M: The aVb3 integrin “vitronectin receptor”. Int J Biochem Cell Biol, 1997, 29(5): 721-725) and the increased concentration of αVβ3 on melanoma cells has been correlated with poor prognosis (Hieken T, Farolan M, Ronan S, Shilkaitis A, Wild L, Das Gupta T: β3 integrin expression in melanoma predicts subsequent metastasis. J Surg Res, 1996, 63(1): 169-173).
Cell surface receptors, that have been linked to cancer, make up an important class of therapeutic targets. Many pharmaceutical companies are actively involved in screening drug libraries for compounds that bind to and block these cell surface receptors. For example, an important drug used to treat breast cancer is Herceptin (Pegram M, Lipton A, Hayes D, Webber B, Baselga J, Tripathy D, Baly D, Baughman S, Twaddell T, Glaspy J, Slamon D: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185 Her2/neu monoclonal antibody plus cisplatin, in patients with Her2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment, J Clin Oncol, 1998, 16(8): 2659-2671). This drug binds to and blocks HER2/neu (Ross J, Fletcher J: review, The Her2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells, 1998, 16(6): 413-428) which is a cell surface receptor that is over-expressed on 30% of breast tumors.
Another cell surface receptor, called MUC1 (Treon S, Mollick J, Urashima M, Teoh G, Chauhan D, Ogata A, Raje N, Hilgers J, Nadler L, Belch A, Pilarski L and Anderson K: MUC1 core protein is expressed on multiple myeloma cells and is induced by dexamethasone. Blood, 1999, 93(4): 1287-1298), is especially interesting since it is aberrantly expressed on many human tumors, including 80% of breast tumors, and on a significant percentage of prostate, lung, ovarian, colorectal and perhaps brain, cancers. On healthy secretory epithelium, MUC1 is clustered at the apical border and is not expressed over other portions of the cell. However, in tumor cells, the receptor is homogeneously over-expressed over the entire cell surface (Kufe D., Inghirami G., Abe M., Hayes D, Justi-Wheeler H, Schlom J: Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. Hybridoma, 1984, 3: 223-232), rather than just at the apical border. It is also known that women with breast cancer have elevated levels of shed MUC1 receptor in their blood stream. Extracellular portions of the MUC1 receptor are cleaved or “shed”, by at least one enzyme, and released into the blood stream. Levels of shed MUC1 receptor in serum are measured to track breast cancer patients for recurrence. However, the method is too variable and insensitive to be used as a general diagnostic.
Until now, the mechanistic link between the MUC1 receptor and tumorigenesis has not been understood. Attempts to correlate the number of repeat units, which varies from person to person, and susceptibility to cancer failed. Investigations of a possible connection, between glycosylation of the MUC1 receptor and cancer, produced conflicting results. Importantly, until now, a functional ligand(s) for the extracellular portion of the MUC1 receptor has not been identified.
Absent an understanding of the mechanism of the MUC1 receptor, and how it triggers tumorigenesis, it has not been possible to design or identify therapeutics that interfere with the disease-associated function of this receptor. Indeed, currently there is no drug in use or, to our knowledge, in clinical trials that is known to target the MUC1 receptor.
The present invention describes discoveries that elucidate critical aspects of the mechanism by which MUC1 triggers cell proliferation and tumorigenesis. These discoveries provide novel molecular targets for drug screening assays which the inventors have used to identify compounds that inhibit the MUC1-dependent tumorigenesis. These discoveries also enable an early diagnostic assay.